Malaria continues to represent a devastating world-wide health problem. Each year, an estimated 500 million people contract malaria, resulting in over 1 million deaths annually (Snow, Guerra et al. 2005). In humans, malaria is caused by the infection with obligate intraerythrocytic protozoa of the genus Plasmodium, and specifically by the infection with one (or more) of the following four species: P. falciparum, P. vivax, P. ovale, and P. malariae. Among these, P. falciparum is responsible for the vast majority of lethal malaria infections. Traditional pharmacological treatments against malaria have involved the use of quinolines (e.g., chloroquine, quinine, mefloquine, primaquine) and antifolates (e.g., sulfadoxine-pyrimethamine). Unfortunately, parasite resistance against one or more of these drugs has emerged in many endemic countries over the past decades, causing a steep resurgence of malaria morbidity and mortality (Eastman and Fidock 2009).
Currently, a most promising class of antimalarial agents is that derived from the naturally occurring sesquiterpene lactone artemisinin (ART, 1), also known as Qinghaosu (Eastman and Fidock 2009).

Artemisinin is extracted from the annual wormwood Artemisia annua and its antimalarial properties were first discovered by Chinese scientists in the early 1970s (White 2008). Artemisinin was found to be highly effective at suppressing the parasitemias caused by P. falciparum and P. vivax, including those caused by multidrug-resistant Plasmodium strains insensitive to conventional antimalarial drugs such as chloroquine and sulfadoxine-pyrimethamine. In addition, artemisinin exhibits several other advantageous features as antimalarial agent such as rapid onset of action, high therapeutic index, and high activity against all of the blood stages of parasite infection, inducing 10- to 100-fold higher reduction in parasitemia per cycle compared to other antimalarial agents (White 2008). It is also active against P. falciparum gametocytes, which are responsible for transmission of the infection and spread of the disease (Chen, Li et al. 1994). Owing to these properties, artemisinin-based therapies constitute a mainstay of the current portfolio of antimalarial drugs and they have been recommended by WHO as first-line treatment for both uncomplicated and severe malaria (Olliaro and Wells 2009).
Current artemisinin-based therapies rely on the semisynthetic, C10-modified artemisinin derivatives artemether (ATM), artesunate (AS), or dehydroartemisinin (DHA), which have improved oral bioavailability and/or water-solubility compared to artemisinin. These derivatives are prepared via chemical reduction of the lactone ring in artemisinin to yield DHA, which can be further transformed into artemether or artesunate via etherification or esterification of the C10 hydroxyl group, respectively.
Despite their viability as antimalarial agents, an important drawback of these semisynthetic artemisinin derivatives is a very short half-life in plasma and in the human body (<1-2 hours) (Navaratnam, Mansor et al. 2000). As a result of this limited metabolic stability, high and repeated doses of these compounds are typically required for a single course of treatment, which contributes to the high costs of ART-based combination therapies (ACTs) and, in turn, to their limited economic accessibility in malaria endemic countries (White 2008). The development of more potent and/or metabolically stable artemisinin derivatives would permit the use of lower and/or less frequent therapeutic dosages, thus providing key advantages compared to currently available artemisinin-based drugs.
In humans, a major route of artemether/artesunate metabolic breakdown involves the rapid conversion of these drugs to DHA via dealkylation or hydrolysis, respectively, of the ether/ester group at C10 (Navaratnam, Mansor et al. 2000; O'Neill and Posner 2004). In addition, these drugs are metabolized by hepatic P450s, resulting in oxidized products carrying hydroxylation(s) at position C7 and C6a (Navaratnam, Mansor et al. 2000; O'Neill and Posner 2004; Haynes, Fugmann et al. 2006). Both these hydroxylated metabolites and DHA are targets of Phase II metabolism (glucuronidation), which further contributes to the fast clearance and excretion of these metabolites (Navaratnam, Mansor et al. 2000; O'Neill and Posner 2004).
In principle, chemical manipulation of metabolically labile positions in the artemisinin structure could provide a means to produce derivatives with improved pharmacokinetic properties and in vivo activity. Yet, the structural complexity of artemisinin, including the presence of a potentially reactive endoperoxide bridge which is essential for antiplasmodial activity, severely limits the range of chemical transformations accessible on this compound.
In part due to these constraints, the vast majority of medicinal chemistry studies carried out on this natural product over the past two decades have focused on modifying position C10 and/or the neighboring site C9, which can be accessed by chemical means. Accordingly, the synthesis and biological evaluation of a large number of C10- and C9-substituted derivatives of artemisinin have been reported (O'Neill and Posner 2004; Chaturvedi, Goswami et al. 2010). Further derivatives of this type and methods for their preparation are described in Venugopalan et al., U.S. Pat. No. 5,225,427 (1993); McChesney et al., U.S. Pat. No. 5,225,562 (1993); Posner et al., U.S. Pat. No. 6,156,790 (2000); Li et al., U.S. Pat. No. 6,307,068 (2001); Posner et al., U.S. Pat. No. 6,586,464 (2003); Begue et al. U.S. Pat. No. 7,417,155 (2008); Posner et al., U.S. Pat. No. 7,417,156 (2008); Begue et al., U.S. Pat. No. 7,696,362 (2010); Haynes et al., U.S. Pat. No. 7,439,238 (2008); Li et al., U.S. Pat. No. 7,910,750 (2011). In some cases, the substitution of the labile C10 ether/ester linkage (as in artemether and artesunate) with non-hydrolizable bonds such as carbon-carbon or carbon-nitrogen bonds has led to artemisinin derivatives with improved antimalarial properties (O'Neill and Posner 2004; Chaturvedi, Goswami et al. 2010). For example, a most promising candidate among the 10-functionalized artemisinin derivatives is the 10-alkylamino derivative artemisone (Haynes, Fugmann et al. 2006). However, C10- (or C9-) substituted artemisinin derivatives remain susceptible to metabolic attack by human liver P450s at the level of the carbocyclic core of the molecule, (Haynes, Fugmann et al. 2006) which can result in somewhat prolonged but still very short in vivo elimination half-lives as observed in the case of artemisone (Nagelschmitz, Voith et al. 2008)
Citation or identification of any reference in Section 2, or in any other section of this application, shall not be considered an admission that such reference is available as prior art to the present invention.